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Identification of novel CLN2 mutations shows Canadian specific NCL2 alleles
  1. W Ju1,2,
  2. R Zhong1,4,
  3. S Moore5,
  4. D Moroziewicz1,2,
  5. J R Currie2,
  6. P Parfrey5,
  7. W T Brown2,
  8. N Zhong1,2,3
  1. 1SCL-Molecular Neurogenetic Diagnostic Laboratory, NYS Institute for Basic Research, 1050 Forest Hill Road, Staten Island, NY, USA
  2. 2Department of Human Genetics, NYS Institute for Basic Research, 1050 Forest Hill Road, Staten Island, NY, USA
  3. 3Department of Neurology, SUNY Downstate Health Center, Brooklyn, NY, USA
  4. 4Stuyvesant High School, New York, NY, USA
  5. 5Clinical Epidemiology Unit, Health Sciences Center, Memorial University of Newfoundland, St John’s, NF, Canada
  1. Correspondence to:
 Dr N A Zhong, SCL-Molecular Neurogenetic Diagnostic Laboratory, NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA;
 ibrsclmndl{at}aol.com

https://doi.org/10.1136/jmg.39.11.822

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    NCL2, the neuronal ceroid lipofuscinosis (NCL) with a classical late infantile onset (LINCL or Jansky-Bielschowsky disease, MIM 204500) is among the most common childhood neurodegenerative disorders. Usually, affected children show generalised tonic-clonic and/or myoclonic seizures starting by 2 to 3 years of age as the initial, and the most noticeable, clinical symptom. This is followed by regressive cognitive dysfunction, including speech delay, slow learning, and mental retardation; neuromotor dysfunction, including ataxia and inability to walk; vision problems; behavioural changes and eventual dementia. Pathological studies by electron microscopy (EM) examination of peripheral blood “buffy coats” and/or tissue biopsy (including skin, conjunctiva, rectal, muscle, brain, or peripheral nerve) have found lysosomal curvilinear (CV) inclusions. These CV inclusions reflect the typical ultrastructural profile of autofluorescent lipofuscin storage materials that consist predominantly of mitochondrial ATP synthase (ATPase) subunit C. Such EM observations are the common basis for the clinical diagnosis of LINCL.1

    Genetically, the gene CLN2 underlying NCL2 has been mapped to chromosome 11p15.2 It consists of 13 exons spanning 6.65 kb of genomic DNA3 and encodes a 46 kDa protein, lysosomal tripeptidyl peptidase 1 (TPP1), which cleaves tripeptides from amino termini of peptides that bear free α-amino groups.4 Mutations in CLN2 abolish TPP1 enzymatic activity in NCL2 patients.5 A total of 42 mutations, which include 10 small deletions/insertions, 20 missense and four nonsense point mutations, and eight splicing errors have been identified (http://www.ucl.ac.uk/ncl).6 We have reported that the heterogeneity of NCL with late infantile onset results from missense mutations in CLN2 that cause atypical onset and clinical symptoms.7

    NCL with late infantile onset has been reported to be common in the population in Newfoundland, Canada,8 but detailed genetic studies are lacking. Here we report molecular genetic analyses of 23 Canadian families that were clinically …

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